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ATP1A3 is a Na,K-ATPase gene expressed specifically in neurons in the brain. Human mutations are dominant and produce an unusually wide spectrum of neurological phenotypes, most notably rapid-onset dystonia parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Here we compared heterozygotes of two mouse lines, a line with little or no expression ( Atp1a 3 tm1Ling/+ ) and a knock-in expressing p.Asp801Tyr (D801Y, Atp1a3 +/D801Y ). Both mouse lines had normal lifespans, but Atp1a3 +/D801Y had mild perinatal mortality contrasting with D801N mice ( Atp1a3 +/D801N ), which had high mortality. The phenotypes of Atp1a 3 tm1Ling/+ and Atp1a3 +/D801Y were different, and testing of each strain was tailored to its symptom range. Atp1a 3 tm1Ling/+ mice displayed little at baseline, but repeated ethanol intoxication produced hyperkinetic motor abnormalities not seen in littermate controls. Atp1a3 +/D801Y mice displayed robust phenotypes: hyperactivity, diminished posture consistent with hypotonia, and deficiencies in beam walk and wire hang tests. Symptoms also included qualitative motor abnormalities that are not well quantified by conventional tests. Paradoxically, Atp1a3 +/D801Y showed sustained better performance than wild type on the accelerating rotarod. Atp1a3 +/D801Y mice were overactive in forced swimming and afterward had intense shivering, transient dystonic postures, and delayed recovery. Remarkably, Atp1a3 +/D801Y mice were refractory to ketamine anesthesia, which elicited hyperactivity and dyskinesia even at higher dose. Neither mouse line exhibited fixed dystonia (typical of RDP patients), spontaneous paroxysmal weakness (typical of AHC patients), or seizures but had consistent, measurable neurological abnormalities. A gradient of variation supports the importance of studying multiple Atp1a3 mutations in animal models to understand the roles of this gene in human disease., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Liu et al.)

Abstract: A 55-year-old man with renal cell carcinoma extending into the renal vein/inferior vena cava (status post nephrectomy and inferior vena cava thrombectomy, pT3bN0M0), and perioperative pulmonary bland thromboembolism (resolved with 3-month of anticoagulation), followed by 3.5 years of complete remission, developed new incidental pulmonary arterial filling defects on a surveillance CT examination (asymptomatic, normal d -dimer, no deep vein thrombosis). Despite anticoagulation, the filling defects not only persisted but also demonstrated intense FDG activity on a restaging PET/CT performed 4 months later for new pulmonary oligometastasis. The FDG activity resolved after systemic immunotherapy, which suggested the retrospective diagnosis of pulmonary arterial tumor emboli, a rare finding., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Early, accurate diagnosis of interstitial lung disease (ILD) informs prognosis and therapy, especially in idiopathic pulmonary fibrosis (IPF). Current diagnostic methods are imperfect. High-resolution computed tomography has limited resolution, and surgical lung biopsy (SLB) carries risks of morbidity and mortality. Endobronchial optical coherence tomography (EB-OCT) is a low-risk, bronchoscope-compatible modality that images large lung volumes in vivo with microscopic resolution, including subpleural lung, and has the potential to improve the diagnostic accuracy of bronchoscopy for ILD diagnosis. Objectives: We performed a prospective diagnostic accuracy study of EB-OCT in patients with ILD with a low-confidence diagnosis undergoing SLB. The primary endpoints were EB-OCT sensitivity/specificity for diagnosis of the histopathologic pattern of usual interstitial pneumonia (UIP) and clinical IPF. The secondary endpoint was agreement between EB-OCT and SLB for diagnosis of the ILD fibrosis pattern. Methods: EB-OCT was performed immediately before SLB. The resulting EB-OCT images and histopathology were interpreted by blinded, independent pathologists. Clinical diagnosis was obtained from the treating pulmonologists after SLB, blinded to EB-OCT. Measurements and Main Results: We enrolled 31 patients, and 4 were excluded because of inconclusive histopathology or lack of EB-OCT data. Twenty-seven patients were included in the analysis (16 men, average age: 65.0 yr): 12 were diagnosed with UIP and 15 with non-UIP ILD. Average FVC and Dl CO were 75.3% (SD, 18.5) and 53.5% (SD, 16.4), respectively. Sensitivity and specificity of EB-OCT was 100% (95% confidence interval, 75.8-100.0%) and 100% (79.6-100%), respectively, for both histopathologic UIP and clinical diagnosis of IPF. There was high agreement between EB-OCT and histopathology for diagnosis of ILD fibrosis pattern (weighted κ: 0.87 [0.72-1.0]). Conclusions: EB-OCT is a safe, accurate method for microscopic ILD diagnosis, as a complement to high-resolution computed tomography and an alternative to SLB.

Adequate tumor yield in core-needle biopsy (CNB) specimens is essential in lung cancer for accurate histological diagnosis, molecular testing for therapeutic decision-making, and tumor biobanking for research. Insufficient tumor sampling in CNB is common, primarily due to inadvertent sampling of tumor-associated fibrosis or atelectatic lung, leading to repeat procedures and delayed diagnosis. Currently, there is no method for rapid, non-destructive intraprocedural assessment of CNBs. Polarization-sensitive optical coherence tomography (PS-OCT) is a high-resolution, volumetric imaging technique that has the potential to meet this clinical need. PS-OCT detects endogenous tissue properties, including birefringence from collagen, and degree of polarization uniformity (DOPU) indicative of tissue depolarization. Here, PS-OCT birefringence and DOPU measurements were used to quantify the amount of tumor, fibrosis, and normal lung parenchyma in 42 fresh, intact lung CNB specimens. PS-OCT results were compared to and validated against matched histology in a blinded assessment. Linear regression analysis showed strong correlations between PS-OCT and matched histology for quantification of tumors, fibrosis, and normal lung parenchyma in CNBs. PS-OCT distinguished CNBs with low tumor content from those with higher tumor content with high sensitivity and specificity. This study demonstrates the potential of PS-OCT as a method for rapid, non-destructive, label-free intra-procedural tumor yield assessment., Competing Interests: LPH: Boehringer Ingelheim, Pliant Therapeutics, LX Medical, and Biogen Idec. MJS: NinePoint Medical, LX Medical., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

The inability to assess and measure changes to the airway smooth muscle (ASM) in vivo is a major challenge to evaluating asthma and its clinical outcomes. Bronchial thermoplasty (BT) is a therapy for asthma that aims to reduce the severity of excessive bronchoconstriction by ablating ASM. Although multiple long-term clinical studies of BT have produced encouraging results, the outcomes of BT treatment in practice have been variable, and questions remain regarding the selection of patients. Previously, we have demonstrated an imaging platform called orientation-resolved optical coherence tomography that can assess ASM endoscopically using an imaging catheter compatible with bronchoscopy. In this work, we present results obtained from a longitudinal BT study performed using a canine model ( n = 8) and with the goal of investigating the use of orientation-resolved optical coherence tomography (OR-OCT) for measuring the effects of BT on ASM. We demonstrate that we are capable of accurately assessing ASM both before and in the weeks following the BT procedure using blinded matching to histological samples stained with Masson's trichrome ( P < 0.0001, r 2 = 0.79). Analysis of volumetric ASM distributions revealed significant decreases in ASM in treated airways (average cross-sectional ASM area: 0.245 ± 0.145 mm 2 pre-BT and 0.166 ± 0.112 mm 2 6 wk following BT). These results demonstrate that OR-OCT can provide clinicians with the feedback necessary to better evaluate ASM and its response to BT, and may potentially play an important role in phenotyping asthma and predicting which patients are most likely to respond to BT treatment. NEW & NOTEWORTHY The inability to assess ASM in vivo is a significant hurdle in advancing our understanding of airway diseases such as asthma, as well as evaluating potential treatments and therapies. In this study, we demonstrate that endoscopic OR-OCT can be used to accurately measure changes to ASM structure following BT. Our results demonstrate how this technology could occupy an important role in asthma treatments targeting ASM.

Background: Accurate diagnosis of idiopathic pulmonary fibrosis (IPF) is essential to inform prognosis and treatment. In 2018, the ATS/ERS/JRS/ALAT and Fleischner Society released new diagnostic guidelines for usual interstitial pneumonitis (UIP)/IPF, adding Probable UIP as a CT category based on prior studies demonstrating this category had relatively high positive predictive value (PPV) for histopathologic UIP/Probable UIP. This study applies the 2018 ATS/ERS/JRS/ALAT and Fleischner Society guidelines to determine test characteristics of CT categories in academic clinical practice., Methods: CT and histopathology were evaluated by three thoracic radiologists and two thoracic pathologists. Comparison of consensus categorization by the 2018 ATS and Fleischner Society guidelines by CT and histopathology was performed., Results: Of patients with CT UIP, 87% (PPV, 95% CI: 60-98%) had histopathologic UIP with 97% (CI: 90-100%) specificity. Of patients with CT Probable UIP, 38% (PPV, CI: 14-68%) had histopathologic UIP and 46% (PPV, CI: 19-75%) had either histopathologic UIP or Probable UIP, with 88% (CI: 77-95%) specificity. Patients with CT Indeterminate and Alternative Diagnosis had histopathologic UIP in 27% (PPV, CI: 6-61%) and 21% (PPV, CI: 11-33%) of cases with specificities of 90% (CI: 80-96%) and 25% (CI: 16-37%). Interobserver variability (kappa) between radiologists ranged 0.32-0.81., Conclusions: CT UIP and Probable UIP have high specificity for histopathologic UIP, and CT UIP has high PPV for histopathologic UIP. PPV of CT Probable UIP was 46% for combined histopathologic UIP/Probable UIP. Our results indicate that additional studies are needed to further assess and refine the guideline criteria to improve classification performance.

The clinical assessment of fibrosis is critical to the diagnosis and management of patients with systemic sclerosis. Current clinical standards for patient assessment is to use skin fibrosis as an indicator of organ involvement, though this approach is highly subjective and relies on manual palpation. The development of a new method for accurately quantifying collagen content may therefore significantly improve the accuracy of the traditional skin score in patients with systemic sclerosis and may additionally aid in the monitoring of anti-fibrotic therapies in clinical practice. Polarization-sensitive optical coherence tomography (PS-OCT) is a high-speed volumetric imaging modality that can be used to assess birefringent tissues including collagen. In this work we demonstrate a novel computational approach using PS-OCT for the assessment of fibrosis. This approach, based on the measured distribution of optic axis values associated with a given volume of collagen orientation, characterizes fibrotic changes independently from the depth of the region of interest in the tissue. This approach has the potential to accurately quantify collagen content and orientation faster and more robustly compared to traditional PS-OCT metrics. We investigate the viability of this approach for assessing the development of fibrosis in a bleomycin induced skin fibrosis mouse model.

Background and Objective: In vivo evaluation of the microstructural differences between asthmatic and non-asthmatic airways and their functional consequences is relevant to understanding and, potentially, treating asthma. In this study, we use endobronchial optical coherence tomography to investigate how allergic airways with asthma differ from allergic non-asthmatic airways in baseline microstructure and in response to allergen challenge., Methods: A total of 45 subjects completed the study, including 20 allergic, mildly asthmatic individuals, 22 non-asthmatic allergic controls and 3 healthy controls. A 3-cm airway segment in the right middle and right upper lobe were imaged in each subject immediately before and 24 h following segmental allergen challenge to the right middle lobe. Relationships between optical airway measurements (epithelial and mucosal thicknesses, mucosal buckling and mucus) and airway obstruction (FEV 1 /FVC (forced expiratory volume in 1 s/forced vital capacity) and FEV 1 % (FEV 1 as a percentage of predictive value)) were investigated., Results: Significant increases at baseline and in response to allergen were observed for all four of our imaging metrics in the asthmatic airways compared to the non-asthmatic airways. Epithelial thickness and mucosal buckling exhibited a significant relationship to FEV 1 /FVC in the asthmatic group., Conclusion: Simultaneous assessments of airway microstructure, buckling and mucus revealed both structural and functional differences between the mildly asthmatic and control groups, with airway buckling seeming to be the most relevant factor. The results of this study demonstrate that a comprehensive, microstructural approach to assessing the airways may be important in future asthma studies as well as in the monitoring and treatment of asthma., (© 2019 Asian Pacific Society of Respirology.)

Low-tidal volume (Vt) ventilation might protect healthy lungs from volutrauma but lead to inflammation resulting from other mechanisms, namely alveolar derecruitment and the ensuing alveolar collapse and tidal reexpansion. We hypothesized that the different mechanisms of low- and high-volume injury would be reflected in different mechanical properties being associated with development of pulmonary inflammation and mortality: an increase of hysteresis, reflecting progressive alveolar derecruitment, at low Vt; an increase of elastance, as a result of overdistension, at higher Vt. Mice were allocated to "protective" (6 ml/kg) or "injurious" (15-20 ml/kg) Vt groups and ventilated for 16 hours or until death. We measured elastance and hysteresis; pulmonary IL-6, IL-1β, and MIP-2 (macrophage inflammatory protein 2); wet-to-dry ratio; and blood gases. Survival was greater in the protective group (60%) than in the injurious group (25%). Nonsurvivors showed increased pulmonary cytokines, particularly in the injurious group, with the increase of elastance reflecting IL-6 concentration. Survivors instead showed only modest increases of cytokines, independent of Vt and unrelated to the increase of elastance. No single lung strain threshold could discriminate survivors from nonsurvivors. Hysteresis increased faster in the protective group, but, contrary to our hypothesis, its change was inversely related to the concentration of cytokines. In this model, significant mortality associated with pulmonary inflammation occurred even for strain values as low as about 0.8. Low Vt improved survival. The accompanying increase of hysteresis was not associated with greater inflammation.

We propose a novel suite of algorithms for automatically segmenting the airway lumen and mucus in endobronchial optical coherence tomography (OCT) data sets, as well as a novel approach for quantifying the contents of the mucus. Mucus and lumen were segmented using a robust, multi-stage algorithm that requires only minimal input regarding sheath geometry. The algorithm performance was highly accurate in a wide range of airway and noise conditions. Mucus was classified using mean backscattering intensity and grey level co-occurrence matrix (GLCM) statistics. We evaluated our techniques in vivo in asthmatic and non-asthmatic volunteers.

The inability to visualize airway smooth muscle (ASM) cells in vivo is a major obstacle in understanding their role in normal physiology and diseases. At present, there is no imaging modality available to assess ASM in vivo. Confocal endomicroscopy lacks the penetration depth and field of view, and conventional optical coherence tomography (OCT) does not have sufficient contrast to differentiate ASM from surrounding tissues. We have developed a birefringence microscopy platform that leverages the micro-organization of tissue to add further dimension to traditional OCT. We have used this technology to validate ASM measurements in ex vivo swine and canine studies, visualize and characterize volumetric representations of ASM in vivo, and quantify and predict ASM contractile force as a function of optical retardation. We provide in vivo images and volumetric assessments of ASM in living humans and document structural disease variations in subjects with mild asthma. The opportunity to link inflammatory responses to ASM responses and to link ASM responses to clinical responses and outcomes could lead to an increased understanding of diseases of the airway and, ultimately, to improved patient outcomes., (Copyright © 2016, American Association for the Advancement of Science.)

Structural and functional longitudinal alterations of the lungs were followed in an emphysema model. Rats were treated with porcine pancreatic elastase (PPE, n=21) or saline (controls, C, n=19). Before the treatment and 3, 10, 21 and 105 days thereafter, absolute lung volumes (FRC, TLC and RV) and tissue mechanical parameters (elastance: H; damping: G) were determined. At 3, 21 and 105 days the lungs were fixed in subgroups of rats. From histological samples the equivalent diameter of airspaces (Dalv), elastin (Mec) and collagen densities were assessed. In the PPE group, FRC and RV were higher from 3 days after treatment compared to controls (p<0.001), while TLC exhibited a delayed increase. H and G decreased in the PPE group throughout the study (p<0.001). Higher Mec (p<0.001) and late-phase inflammation were observed at 105 days. We conclude that during the progression of emphysema, septal failures increase Dalv which decreases H; this reveals a strong structure-function relationship., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Transpulmonary pressure and the mechanical stresses of breathing modulate many essential cell functions in the lung via mechanotransduction. We review how mechanical factors could influence the pathogenesis of emphysema. Although the progression of emphysema has been linked to mechanical rupture, little is known about how these stresses alter lung remodeling. We present possible new directions and an integrated multiscale view that may prove useful in finding solutions for this disease.

The relation between the progression of chronic obstructive pulmonary disease (COPD) and exacerbations is unclear. Currently, no animal model of acute exacerbation of COPD (AECOPD) exists. The objectives of this study were to evaluate the effects of mechanical forces induced by deep inspirations (DIs) on short-term deterioration of lung structure and function to mimic AECOPD. At 2, 7, or 21 days after treatment with elastase, mice were ventilated with or without DIs (35 cmH(2)O airway pressure for 3 s, 2 times/min) for 1 h. Functional residual capacity (FRC) was measured with body plethysmography, and respiratory compliance, resistance, and hysteresivity were obtained via forced oscillations. From hematoxylin and eosin-stained sections, equivalent airspace diameters (D), alveolar wall thickness (W(t)), number of septal ruptures (N(sr)), and attachment density (A(d)) around airways were determined. FRC, compliance, and hysteresivity statistically significantly increased with time, and both increased due to DIs. Interestingly, DIs also had an effect on FRC, compliance, resistance, and hysteresivity in control mice. The development of emphysema statistically significantly increased D and W(t) in time, and the DIs caused subtle differences in D. At 21 days, the application of DIs changed the distribution of D, increased W(t) and N(sr), and decreased A(d). These results suggest that once a critical remodeling of the parenchyma has been reached, acute mechanical forces lead to irreversible changes in structure and function, mimicking COPD exacerbations. Thus, the acute application of DIs in mice with emphysema may serve as a useful model of AECOPD.

The aim of this study was to evaluate airway structure-function relations in elastase-induced emphysema in rats. Sprague-Dawley rats were treated intratracheally with 50 IU porcine pancreatic elastase (PPE, n = 8) or saline (controls, n = 6). Six weeks later, lung volumes [functional residual capacity (FRC), residual volume (RV), and total lung capacity (TLC)] and low-frequency impedance parameters (Newtonian resistance, R(N); tissue damping; tissue elastance, H) were measured, and tracheal sounds were recorded during slow inflation to TLC following in vivo degassing. The lungs were fixed and stained for standard morphometry, elastin, and collagen. In the PPE group, FRC and RV were higher [4.53 ± 0.7 (SD) vs. 3.28 ± 0.45 ml; P = 0.003 and 1.06 ± 0.35 vs. 0.69 ± 0.18 ml; P = 0.036, respectively], and H was smaller in the PPE-treated rats than in the controls (1,344 ± 216 vs. 2,178 ± 305 cmH(2)O/l; P < 0.001), whereas there was no difference in R(N). The average number of crackles per inflation was similar in the two groups; however, the crackle size distributions were different and the lower knee of the pressure-volume curves was higher in the PPE group. Microscopic images revealed different alveolar size distributions but similar bronchial diameters in the two groups. The treatment caused a slight but significant decrease in the numbers of alveolar attachments, no difference in elastin and slightly increased mean level and heterogeneity of collagen in the bronchial walls. These results suggest that tissue destruction did not affect the conventionally assessed airway resistance in this emphysema model, whereas the alterations in the recruitment dynamics can be an early manifestation of impaired airway function.

Absolute lung volumes such as functional residual capacity, residual volume (RV), and total lung capacity (TLC) are used to characterize emphysema in patients, whereas in animal models of emphysema, the mechanical parameters are invariably obtained as a function of transrespiratory pressure (Prs). The aim of the present study was to establish a link between the mechanical parameters including tissue elastance (H) and airway resistance (Raw), and thoracic gas volume (TGV) in addition to Prs in a mouse model of emphysema. Using low-frequency forced oscillations during slow deep inflation, we tracked H and Raw as functions of TGV and Prs in normal mice and mice treated with porcine pancreatic elastase. The presence of emphysema was confirmed by morphometric analysis of histological slices. The treatment resulted in an increase in TGV by 51 and 44% and a decrease in H by 57 and 27%, respectively, at 0 and 20 cmH(2)O of Prs. The Raw did not differ between the groups at any value of Prs, but it was significantly higher in the treated mice at comparable TGV values. In further groups of mice, tracheal sounds were recorded during inflations from RV to TLC. All lung volumes but RV were significantly elevated in the treated mice, whereas the numbers and size distributions of inspiratory crackles were not different, suggesting that the airways were not affected by the elastase treatment. These findings emphasize the importance of absolute lung volumes and indicate that tissue destruction was not associated with airway dysfunction in this mouse model of emphysema.